Genetic targeting of ERK1 suggests a predominant role for ERK2 in murine pain models.
Genetic targeting of ERK1 suggests a predominant role for ERK2 in murine pain models.
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DOI：
10.1523/jneurosci.6103-09.2010
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发表时间：
2010-08-25
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影响因子：
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通讯作者：
Gereau RW 4th
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文献类型：
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作者：
Alter BJ;Zhao C;Karim F;Landreth GE;Gereau RW 4th
细胞外信号调节激酶（ERK）亚型，ERK 1和ERK 2，被认为是伤害感受和伤害感受敏化的关键信号分子。利用靶向共有的ERK 1/2上游激活剂、丝裂原活化蛋白激酶激酶（MEK）和表达显性阴性形式MEK的转基因小鼠的抑制剂的研究已经确立了ERK 1/2信号传导的重要性。然而，这些技术不能区分ERK 1和ERK 2。为了剖析每种亚型在疼痛中的功能，我们利用ERK 1靶向基因缺失（ERK 1 KO）的小鼠来测试ERK 1是啮齿动物疼痛模型中行为敏化所需的假设。尽管激活（磷酸化）的ERK 1急性伤害性刺激和慢性疼痛的模型，我们发现，ERK 1是不需要福尔马林诱导的自发行为，完全弗氏佐剂诱导的热和机械过敏，和备用神经损伤诱导的机械过敏。然而，ERK 1缺失确实延迟了福尔马林诱导的长期热超敏反应，而不影响福尔马林诱导的机械超敏反应，这表明ERK 1部分地塑造了对福尔马林的长期反应。有趣的是，ERK 1缺失导致基础ERK 2磷酸化水平升高。然而，这似乎并没有影响伤害性处理，因为炎症诱导的ERK 2磷酸化和pERK 1/2免疫反应性在脊髓中没有升高ERK 1 KO小鼠。此外，在WT和ERK 1 KO小鼠中，SL 327全身性MEK抑制可类似地减弱福尔马林诱导的自发行为，表明不相关的信号传导途径不能在功能上补偿ERK 1的损失。两者合计，这些结果表明，ERK 1在伤害性敏化中起着有限的作用，并支持ERK 2在这些过程中的主导作用。
The extracellular signal-regulated kinase (ERK) isoforms, ERK1 and ERK2, are believed to be key signaling molecules in nociception and nociceptive sensitization. Studies utilizing inhibitors targeting the shared ERK1/2 upstream activator, mitogen-activated protein kinase kinase (MEK), and transgenic mice expressing a dominant negative form of MEK have established the importance of ERK1/2 signaling. However, these techniques do not discriminate between ERK1 and ERK2. To dissect the function of each isoform in pain, we utilized mice with a targeted genetic deletion of ERK1 (ERK1 KO) to test the hypothesis that ERK1 is required for behavioral sensitization in rodent pain models. Despite activation (phosphorylation) of ERK1 following acute noxious stimulation and in models of chronic pain, we found that ERK1 was not required for formalin-induced spontaneous behaviors, complete Freund’s adjuvant-induced heat and mechanical hypersensitivity, and spared nerve injury-induced mechanical hypersensitivity. However, ERK1 deletion did delay formalin-induced long-term heat hypersensitivity, without affecting formalin-induced mechanical hypersensitivity, suggesting that ERK1 partially shapes long-term responses to formalin. Interestingly, ERK1 deletion resulted in elevated basal ERK2 phosphorylation. However, this did not appear to influence nociceptive processing, since inflammation-induced ERK2 phosphorylation and pERK1/2 immunoreactivity in spinal cord were not elevated in ERK1 KO mice. Additionally, systemic MEK inhibition with SL327 attenuated formalin-induced spontaneous behaviors similarly in WT and ERK1 KO mice, indicating that unrelated signaling pathways do not functionally compensate for the loss of ERK1. Taken together, these results suggest that ERK1 plays a limited role in nociceptive sensitization and supports a predominant role for ERK2 in these processes.